The measurement of serum prostate specific antigen (PSA) is widely used for the screening and early detection of prostate cancer (PCa). As discussed in the public report “Polygenic Risk Score Improves Prostate Cancer Risk Prediction: Results from the Stockholm-1 Cohort Study” by Markus Aly and co-authors as published in EUROPEAN UROLOGY 60 (2011) 21-28 (which is incorporated by reference herein), serum PSA that is measurable by current clinical immunoassays exists primarily as either the free “non-complexed” form (free PSA), or as a complex with a-lantichymotrypsin (ACT). The ratio of free to total PSA in serum has been demonstrated to significantly improve the detection of PCa. Other factors, like age and documented family history may also improve the detection of PCa further. The measurement of genetic markers related to PCa, in particular single nucleotide polymorphisms (SNP), is an emerging modality for the screening and early detection of prostate cancer. Analysis of multiple PCa related SNPs can, in combination with biomarkers like PSA and general information about the patient, improve the risk assessment through a combination of several SNPs into a genetic score, as described in the patent publication WO2013172779 (which is incorporated by reference herein). The screening and early detection of prostate cancer is a complicated task, and to date no single biomarker has been proven sufficiently good for specific and sensitive mapping of the male population. Therefore, attempts have been spent on combining biomarker levels in order to produce a formula which performs better in the screening and early detection of PCa. The most common example is the regular PSA test, which in fact is an assessment of “free” PSA and “total” PSA. Another such example is the use of combinations of concentrations of free PSA, total PSA, and one or more pro-enzyme forms of PSA for the purpose of diagnosis, as described in WO03100079 (METHOD OF ANALYZING PROENZYME FORMS OF PROSTATE SPECIFIC ANTIGEN IN SERUM TO IMPROVE PROSTATE CANCER DETECTION) which is incorporated by reference herein. The one possible combination of PSA concentrations and pro-enzyme concentrations that may result in improved performance for the screening and early detection of PCa is the phi index. Phi was developed as a combination of PSA, free PSA, and a PSA precursor form [−2]proPSA to better detecting PCa for men with a borderline PSA test (e.g. PSA 2-10 ng/mL) and non-suspicious digital rectal examination, as disclosed in the report “Cost-effectiveness of Prostate Health Index for prostate cancer detection” by Nichol M B and co-authors as published in BJU Int. 2011 Nov. 11. doi: 10.1111/j.1464-410X.2011.10751.x. which is incorporated by reference herein. Another such example is the combination of psp94 and PSA, as described in US2012021925 (DIAGNOSTIC ASSAYS FOR PROSTATE CANCER USING PSP94 AND PSA BIOMARKERS).
There are other biomarkers of potential diagnostic or prognostic value for assessing if a patient suffers from PCa, including MIC-1 as described in the report “Macrophage Inhibitory Cytokine 1: A New Prognostic Marker in Prostate Cancer” by David A. Brown and co-authors as published in Clin Cancer Res 2009; 15(21):OF1-7, which is incorporated by reference herein.
One method used for monitoring of an individual with respect to risk for PCa is to estimate “PSA doubling time”, i.e. measuring the PSA value at different time points (at least two) and based on the PSA values calculating the theoretical time it would take to increase the PSA value from one unit to two units. One example of the use of PSA doubling time for individuals with a PCa diagnosis is described in the article “PSA doubling time as a progression criterion in an active surveillance programme for patients with localised prostate cancer.” by Thomsen F B, Christensen I J, Brasso K, Røder M A, and Iversen P as published in BJU Int. 2013 Jul. 19. doi: 10.1111/bju.12367, which is incorporated by reference herein. In brief, this report describes the potential use of PSA doubling time as a progression criterion in patients with low-risk prostate cancer managed on active surveillance. A PSA doubling time less than 3 years was considered high risk, 3-5 years was intermediate risk, and PSA doubling time greater than 5 years was considered low risk. Definitive treatment was recommended to high-risk patients and treatment options were discussed with intermediate-risk patients. However, the report concluded that the uncertainty of calculated PSA doubling time during active surveillance results in a significant risk of patients being misclassified according to the progression risk definitions, which subsequently limits its use in the management of patients on active surveillance. Hence, there is room for improvement of methods for monitoring individuals with risk for disease progression.
The current performance of the PSA screening and early detection is approximately a sensitivity of 80% and specificity of 30%. It is estimated that approximately 65% will undergo unnecessary prostate biopsy and that 15-20% of the clinically relevant prostate cancers are missed in the current screening. In the United States alone, about 1 million biopsies are performed every year, which results in about 192 000 new cases being diagnosed. Hence, also a small improvement of diagnostic performance will result both in major savings in healthcare expenses due to fewer biopsies and in less human suffering from invasive diagnostic procedures.
The current clinical practice (in Sweden) is to use total PSA as biomarker for detection of asymptomatic and early prostate cancer. The general cutoff value for further evaluation with a prostate biopsy is 3 ng/mL. However, due to the negative consequences of PSA screening there is no organized PSA screening recommended in Europe or North America today.
All in all, this leads to a large number of individuals being tested regularly for the presence of a variety of cancers, causing stress for the individuals and adding cost to the health care system. It is also possible that individuals with clearly elevated predisposition for a particular cancer disease should have even more frequent doctor's appointments than what is currently common.
It is particularly important to accurately identify aggressive prostate cancer (aPCa) in individuals because the sooner an individual is provided treatment, the greater likelihood of the cancer being cured. The identification of aPCa is however difficult, partly because larger cohorts are required to provide a sufficient number of cases and controls in the development of statistical models. Hence, the availability of predictive models for aPCa is low.